Cocaine withdrawal (and withdrawal from other drugs) is associated with CNS disturbances which are reflected in altered neurohormonal secretion, secondary to CNS neurotransmitter alterations. In men known to be cocaine abusers, the secretion of neurohormones has been examined during cocaine withdrawal. Prolactin secretion is under tonic inhibition by dopamine from the hypothalamus. The neurotransmitter most closely associated with cortisol release is serotonin. In the volunteers withdrawn from cocaine, prolactin levels were higher than in men who had not ever taken cocaine, and the diurnal rhythms in prolactin secretion were disturbed. The men were followed for up to 21 days with little change in the profiles of prolactin release. Cortisol levels and rhythms were similar to controls over this withdrawal period. These results suggest that chronic cocaine abuse results in dysfunction of dopamine mediated mechanisms of neurosecretion. The alterations in the hypothalamo-pituitary-adrenal axis resulting from chronic cocaine abuse, is being further defined. This will enable study in volunteers whose serotonergic and dopaminergic functions are predictably manipulated, with tests that perturb the hypothalamic-pituitary-adrenal axis at a known level. Standard endocrine diagnostic tests (TRH, CRF stimulation and L-dopa suppression) in conjunction with drugs that perturb dopaminergic and serotonergic function have been carried out. The study will provide further information on dopaminergic control of hormonal secretion and its role in maintaining diurnal rhythms of hormones. It may provide an important means of assessing the efficacy of treatment protocols. Mechanisms of these changes is being investigated in a rat model of cocaine withdrawal.